Monoacylglycerol lipase (MAGL) has an essential role in the catabolic pathway of the endocannabinoid 2-arachidonoylglycerol, which makes it a potential target for highly specific inhibitors for the treatment of a number of diseases. We designed and synthesized a series of carbamate analogues of URB602. We evaluated their inhibitory activity toward human MAGL in vitro both in cell culture and lysates. The target compounds exhibited moderate to excellent inhibitory activity against MAGL. The most promising compound 2b showed good inhibitory activity with IC50value of 4.5 ± 0.70 μM reducing MAGL activity to 82% of controls at 10 μM compared to 66% for the parent compound URB602. Interestingly, compounds 2b and 2c induce cell death through the inhibition of MAGL. Molecular modelling approaches and docking studies, used to investigate inhibitory profiles, indicated that trifluoromethyl substitutions of the aryl group and the benzene ring present at the oxygen side of the carbamate molecule had a significant impact on the activity.
Design, synthesis, molecular modelling and in vitro cytotoxicity analysis of novel carbamate derivatives as inhibitors of Monoacylglycerol lipase / S. Lauria, C. Perrotta, S. Casati, I. Di Renzo, R. Ottria, I. Eberini, L. Palazzolo, C. Parravicini, P. Ciuffreda. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 26:9(2018 May 15), pp. 2561-2572.
|Titolo:||Design, synthesis, molecular modelling and in vitro cytotoxicity analysis of novel carbamate derivatives as inhibitors of Monoacylglycerol lipase|
LAURIA, SIMONE (Primo)
PERROTTA, CRISTIANA (Secondo)
CIUFFREDA, PIERANGELA (Ultimo) (Corresponding)
|Parole Chiave:||anti-proliferative; carbamate; cytotoxicity; monoacylglycerol lipase; structure-activity relationships; biochemistry; molecular medicine; molecular biology; 3003; drug discovery3003 pharmaceutical science; clinical biochemistry; organic chemistry|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
Settore BIO/14 - Farmacologia
|Data di pubblicazione:||15-mag-2018|
|Data ahead of print / Data di stampa:||12-apr-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bmc.2018.04.024|
|Appare nelle tipologie:||01 - Articolo su periodico|